15-alkyl steroids



United States Patent 3,116,304 IS-ALKYL STEROIDS David Taub, Metuchen, and Norman L. Wendler, Summit, N.J., assignors to Merck & Co., Inc., Railway, N.J., a corporation of New Jersey No Drawing. Filed Nov. 2, 1961, Ser. No. 149,499 9 Claims. (Cl. 260-39145) This invention relates to IS-alkyl steroids. More specifiically, this invention relates to ll-oxygenated 15-alkyl steroids of the pregnane series and to compounds of the formula in which R, R and R are each hydrogen or alkyl, R may be hydrogen, halogen or alkyl, R can be hydrogen or lower alkanoyl, X may be hydrogen, halogen and together with Y a 9,11 double bond, Y may be fi-hydroxyl, keto oxygen and together with X a 9,11 double bond, the dotted line in ring A indicates either a single or double C C bond and the wavy lines at carbons 15 and 16 indi cate either a or 5 substituents. More specifically, also, this invention relates to new steroid intermediates, especially compounds of the formula CHzOH 3,11%,394 Patented Dec. 31, 1963 "Ice in which R may be a or ,G-alkyl and also to compounds of the formula in which R and R may be hydrogen or alkyl, R may be hydrogen or lower alkanoyl and the 15 and 16 substituents may be 0a or B as shown by the wavy lines.

We have found that the introduction of an alkyl group at the 15 position of the pregnane nucleus produces a wide variety of new steroids of great utility.

The 15-a1kyl steroids produced in accordance with the present invention possess high anti-inflammatory activity, considerably greater than that of the parent steroids, and are especially efiective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesired side effects.

In the preparation of the new anti-inflammatory steroids of our invention, one can start with 3a,l7e,21-trihydroxy-pregnane-l1,20-diones, either with or without a 1604 or fl-alkyl group. Likewise, the corresponding 5apregnane derivatives are also usable as starting materials and the term pregnane in these specifications and claims are intended to cover these isomeric compounds. When the starting material is 3a,17a,2l-trihydroxy-pregnane-S, 11,20-dione itself, or the or fl-alkyl derivatives thereof, the prime intermediate, the 15-keto compound may be prepared by microbial oxidation, This is described in Flow Sheet I. The 3 and 2l-hydroxyls are protected as the Z-tetrahydropyranyl ethers and the microbial oxidation to a hydroxyl, described in US. Letters Patent 2,960,- 434, is then followed. The hydroxyl thus introduced at 15 is oxidized to a keto group followed by removal of the protecting group.

Biological Preparation of 3a,] 7a,21Trihydr0xypregna- 11,15,20-Tri0nes ofj m egg See footnotes at end of table.

(llHzOH 00 Definitions O H 1W R3 H O C U R :H or alkyl, Reagents (1) 2,3-dihydropyran in ether, HCI catalyst at room temperature (0H et al, J. Am. Chem. 300., 74, 1219 (1952)).

(2) Microbiological oxidation with an oxidizing strain of B. megatem'mn (NRRL 2471). (Cf. U.S. 2,960,424.)

(3) C1303 in pyridine,

(4) H01 in aq. alcohol at reflux.

When the starting material is a 16-a1kyl-3u,l7a,2l-trihydroxy-pregnane-l1,20-dione such as the 160: or fl-metlr yl, 16a 0r B-ethyl, 1611 or [i-propyl or 1604 or 18-butyl it LE -CU compounds, the introduction of a IS-keto in order to form 40 the primary intermediate may alternatively be carried out by a series of chemical reactions as described in Flow CHzO Sheet II, By a series of known reactions, the IS-bromo- 16,17-oxido compound is synthesized in one of two ways as shown in the flow sheet. The 15-br0mo is then replaced with an acetoxy group and the oxido ring reopened to reform the 17a-hydr0xyl. In so doing, there is formed a l5,l6-double bond which is part of an enol acetate structure. Saponification of the acetate radical causes deenolization to the IS-keto compounds. The acetate is usually preferred, but any other lower alkanoyloxy group is usually usable. The 15-keto-l6-alky1 steroids which are thus obtained (compounds S and T in Flow Sheet II) are the 16m and 16p epimers. These may be separated at this point if desired.

Preparation of 3a,] 7:1,21 -T rilzydroxy-J 6-Alkylpregna- See footnotes at end of table.

o gm U 1,15,20-Tri0nes CHzOAC lCHzOH C O ('30 I "0H 0 j wrotum HO- CHzOAc ICHzOAC CO moon CHzOH (130 M ---OH 0 41mm of]: Toma Definitions I t 1 Whether or not there is present a 16-alkyl group, the

R zl l or alkyL l-keto steroid is then converted to a mlxture of 150: and gi hue shws a mlxture of a Substltuents' l5fi-alkyl steroids by the chemical reactions shown in 1 A ueous caustic (KOH, NaOH, NazCOs, etc.).

2) S micarbazide hydrochloride and NaHCOa in aque- Flow HI, These consist first protecimg the 3 A or rs dlIlllettllnilifmmagnldefi he t C substituents in the form of a bismethylenedioxy den1 1' ,aceicacl, a.

(4; P soi id e or fidati onalkaline H202 or alkyl hydro- 11Vat1v followed y condensatlon of the 154mm group peroxide and base followed by reacylation at C3 or an organic peracid such as CFaCOsH.

HCl and acetic acid.

Separation by recrystallization.

N -bromosuccinimide in t-butanol.

HBr in acetic acid.

rPotassium acetate (other potassium alkanoates give the equlvalent corresponding alkanoyloxy derivative) (10) Strong acid (HBr, HCl, HF, HC104, CFaCOOH,

(11) Sodium hydroxide in aqueous methanol.

Note.The starting material (Compound E), when R H, is reported by Taub et al. (J. Am. Chem. Soc, 82, 4012 (1960)). By using higher diazoalkanes such as diazoethane, diazopropane, diazobutane, etc. in the process reported there, in place of diazomethane, the corresponding IG-higher alkyl starting materials are obtained.

(S and/or T) with an alkylidene triphenylphosphine to form a 15-alkylidene compound. Catalytic hydrogenation of this gives a mixture of 15a and ,B-alkyl groups which may be separated by chromatography. Thus, in the absence of 16- alkyl groups, one obtains both l5-epimers, and, when the a and ,8 16-alkyl starting materials are used, the four possible stereo isomers are obtained. In this process, any alkylidene triphenylphosphine is usable such as the ethylidene, propylidene, butylidene, etc. compounds, but, in general, We prefer to use the simplest, namely, methylene triphenylphosphine ether.

Preparation of 15-Alkyl Compounds O-CH: 2O

See footnotes at end of table.

O-GHi O-CHa mo me I o-o-0 0-o-o CH2 CH2 MN 32 O W R2 MN CHaR CHR Definfitigs z alkyl oxidize the 3-hydroXyl to a keto group. This is done he- R2;H -a1k 1 fore removing the bismethylenedioxy substitutent which g a i rs li s s w either or both a and fl-substitutionhas been placed on the nucleus to protect the side chain (1) Formaldehyde, HCl, CHCla, substituents. The 3-keto compound is then treated to (2) Alkylidene triphenylphosphine. 20

(3) Catalytic hydrogenation (e.g., H2 over Pd). Note-30th the 16 and 15-alky1 groups may be either or or B. The 16-alky1 epimers, when present, are separated earlier. (Cf. Flow Sheet II.) The 15-a1ky1 epimers of each can be separated at the end of the above sequence by chromatography. Thus, all four possible 15,16-dialky1 compounds or both 15-a1ky1 compounds are obtained.

These IS-alkyl intermediates are converted by standard methods to anti-inflammatory steroids as described in Flow Sheet IV. The IS-alkyl steroids still have a saturated ring A and a hydroxyl at carbon three. It is, therefore,

remove the bismethylenedioxy group followed by acylation of the 2l-hydroxyl with a lower alkanoyl group for protection, to produce compound Y of Flow Sheet IV. It is these compounds which are claimed as intermediates since they are useful for the preparation of other steroids than the anti-inflammatory ones. Unsaturation is now introduced into ring A by bromination and reaction with semicarbazide. Then, by standard known reactions, the C keto group is reduced to a hydroxyl in order to permit necessary first, as shown in Part (a) of Flow Sheet IV, to 30 the introduction of other substituents.

Synthesis of 15-Alkyl Anti-Inflammatory Steroids See footnotes at end of table.

f M 011m W W CHIR C:H5OOCG 12) CaHs-O 00-0- See footnotes at end of table.

OH "OH O R M R3 -'NW DHgR' 1 NW OH R /g\/ (6) R (BM) (BN) 1 2 1'1 (e) ALTERNATIVE OTHER TRANSFORMATIONS CHIOR (EH R5 ---0H 110 1m R Nw OHzR' Rt m) (AF) (AV) (A L) D or (BB) after 15 4 OH HO l R MN GHIRI (31 1 0131- CHaOH 00 oo --o11 ---0H o=f i: 1m R: HO Tm R1 W 011m -w oma' Rifily in O 0 I (Be) (B P) 4 CHaOH R 01 :D (BR) Definitions: (12) An alkyl halide (usually methyl iodide which R'=H or alkyl. gives R CHa) in acetone. R=H or alkyl. (13) NaOCHa in absolute alcohol. R3:H or alkyl(1n IV(b) it is used for alkyl only). (14) Formic acid and NaHCOa at 100 followed by R 215, halogen, alkyl-fln IV (b) it is used for alkyl only). NaOCHa in CHaOH at room temperature. R :lower alkanoyL-(m claims it is used for H or lower (15)! )A lower alkanoic anhydrld (usually acetlc anhyalkanoyl). Klride which gives R =acetyl). Wavy lines indicate either a or B substitution. (16) Eethylene glycol and p-toluene sulfonic acid mono- Reagents: hydrate at reflux in benzene.

1) CrOs in pyridine at room temperature. 6 (17) Perbenzoic acid in benzene. (2) Tormlc acid and NaHCOa at 100 followed by 5 (18) BE: in ether and benzene.

NaOcHa in CHQOH at r temperature and (19) ISodium borohydride in tetrahydrofuran and water. then by a lower alkanoic anhydrlde a-t 100 C. (20) p-Toluene sulfonic acid in acetone. 1 Usually acetic anhydilde is used. (21) Sodium borohydride in tetrahydrofuran and water (3) Bra in chloroform on a chloroform-acetic acid sofollowed by Na HPOa on. (22) An alkyl magneslum bromide (RMgBr) (usually (4) lSemicarbazide hydrochloride and NaHCO; in CHaMgBr which gives R :CHa) in ether and water. I benzene. (5) Acetic acid and pyruvlc acid. .(23) Sulfuric acid (98%) in methanol at reflux. ENaHCOa in aqueous methanol. 5(24) [KOH in methanol. (7) Semicarbazide hydrochloride and NaHCOs in aque- (25) CHaSOzCI in dimethylformamide and pyridine.

ous DMF. (26) N-bromosuccinimide in dloxane, plus perchloric (8) !Na bprohydrlde in tetrahydrofuran. acid, at 15 C. Acetlc acid and pyruvic acid. (27) Potassium acetate in absolute alcohol at reflux. 10) Formaldehyde and HCl in chloroform. (28) HF in tetrahydrofuran. NaOCHa and diethyl oxalate in 5-buty1 alcohol, (29) S802 in t-butanol.

In Part (b) of Flow Sheet IV is shown the introduction of Za-alkyl groups, which proceeds through a bismethyllenedioxy derivative, by acylation at position 2 to form a keto ester, followed by reaction with an alkyl halide. Any alkyl halide such as methyl bromide, ethyl iodide, propyl bromide, butyl bromide and the like, may be used, but methyl halide is preferred since it gives the simplest alkyl derivative.

In Part of Flow Sheet IV is described the introduction of 6tx-alkyl or halogen groups. This can be carried out alternatively or successively to the introduction of 2 u-alkyl groups. It is eifected again by protection of the 17 substituents as a bismethylenedioxy group followed by protection of the B-keto groups as an ethylenedioxy group. The latter shifts the C double bond into the 5,6 position which is then utilized to form a 5,6-oxide and by a series of reactions, as described in the flow sheet, this is used to introduce either a halogen or an alkyl group. The halogen is introduced by reaction with chlorine, bromine, etc. or B1 the latter is preferred. An alkyl group is introduced using an alkyl (such as methyl, ethyl, butyl, etc.) magnesium bromide. Methyl magnesium bromide is usually used.

Whether or not 2a-alkyl and/or 6a alkyl or halogen groups have been introduced, the 15-methyl steroids can be further transformed into other anti-inflammatory steroids by dehydration of the ll-hydroxyl to form a 9,11 double bond and, by standard procedures, the introduction of a 9a-fluoro or other halogen. All of these derivatives can be used in the form of an llfi-hydroxyl or an 11- keto and in the form of a free C hydroxyl or a C allranoyl derivative. Any of these compounds as shown in Parts (d) and (e) of Flow Sheet IV can be converted into a A steroid by oxidation with selenium dioxide and these compounds likewise can be used in the form of 11/3- hydroxyl or ll-keto compounds. The details of these various transformations are described in the flow sheet and can be found in the examples.

Among the anti-inflammatory steroids included within our invention can be mentioned:

15-methyl-17oc,2l-dihydroxy 4 pregnene-3,l1,20-trione;

15-methyl 17o,2l dihydroxy 1,4-pregnadiene-3,11,20-

trione;

15-rnethyl 9a fluoro-17a,21-dihydroxy-1,4-pregnadiene- 3,11,20-trione;

15,16-dimethyl 1704,21 dihydroxy-4-pregnene-3,11,20-

trione;

15,16-dimethy1-17a,2l-dihydroxy 1,4 pregnadiene-3,11,

20-trione;

15,16-dirnethyl 90: fluoro-170,21-dihydroxy-1,4-pregnadiene-3,1 1,20-trione;

2,15-dimethyl 170:,21 dihydroxy-l,4-pregnadiene-3,1l,

ZO-trione;

2,15-dimethyl 90 fluoro-l7a,2l-dihydroXy-l,4-preguadiene-3,l1,20-trione;

6,15-dimethyl 170:,21 dihydroxy-l,4-pregnadiene-3,l1,

ZO-trione;

6,15-dimethyl 9a fluoro-l7ot,21-dihydroxy-1,4-pregnadiene-3,l1,20-trione;

2,15,16-trimethyl 1701,21 dihydroxy-1,4-pregnadiene- 3,1 1,2O-trione;

2,15,16-trimethyl 9oz fluoro-l70,2l-dihydroxy-lA-pregnadiene-3,1 1,20-trione;

2,6,15,16-tetramethyl 1711,21 dihydroxy-1,4-pregnadiene-3,1*1,20-trione;

2,6,15,16-tetramethyl 9a fluoro-l7a,21-dihydroxy-1,4-

pregnadiene-3 ,11,20-trione and the corresponding 50: or allopregnane compounds.

Among the intermediates of the two classes claimed as part of our invention can be mentioned:

l6a-methyl-3 a,17o,2l-trihydroxypregna-l1,15,20-trione;

165-methyl-3 a,17a,2l-trihydroxypregna-l1,15,20-trione;

l a-methyll7a,2 1 -dihydroxypregna-3,l 1,20-trione;

15oz,16p-dimethyl-17a,21-dihydroxypregna-3,11,20-trione;

22 15,8-methyl- 17DL,2 1 -dihydroxypregna-3, l 1,20-trione; 155,16a-dimethyl-17a,21-dihydroxypregna-3,1 1,20-trione; 15B,16t3-dimethyl-l7u,2l-dihydroxypregna-3,l1,20-di0ne;

and the corresponding 5 or or allo-pregnane compounds.

Although the flow sheets show the preparation of 15- alkyl-2l-hydroxypregnane derivatives, the same transformations can be carried out on pregnane derivatives lacking the 21-hydroxyl or even the 17u-hydrox'yl. In the latter case the products will be 15-alkyl progesterone derivatives, e.g.

The l5-alkyl steroids, which possess extremely high anti-inflammatory activity, may be administered orally, parenterally or topcially. Thus, the active ingredient can be administered alone or may be associated with a carrier. A smaller quantity of the active l5-alkyl steroid may be administered to the patient and have the same therapeutic efiect as larger quantities of other steroids such as cortisone or hydrocortisone. Any of the carriers used in pharmaceutical practice may be employed where there is no incompatibility with the active materials. The composition may take the form of tablets, powders, capsules, elixirs, syrups or other dosage forms which are particularly useful for oral ingestion. Liquid diluents are employed in sterile condition for parenteral use, namely, by injection. Such a medium may be a sterile solvent for the active material. For topical administration any of the known dermatologic vehicles may be employed. Such vehicles for external application include water-soluble ointment bases, oils, petrolatum and jellies.

Our invention can be illustrated by the following examples:

EXAMPLE 1 a d only To a solution of 1.1 g. of 3a,l7a,2l-trihydroxypregname-11,20-dione in 10 cc. of anhydrous, peroxide-free diethyl ether is added 2.0g. of 2,3-dihydropyran (freshly distilled from NaOH pellets) followed by one drop of concentrated hydrochloric acid. The mixture is allowed to stand several days. The ether is removed by distillation and the residue is dried in vacuo. The residue is used in further reactions as is.

EXAMPLE 2 c am-- on L--OH turbo agitator at 408 r.p.m. and air is passed in at a rate of two liters per minute for approximately 24 hours while maintaining the temperature at 28 C. At the end of the 24-hour period approximately 0.8 g. of the product of Example 1 dissolved in 100 ml. of propylene glycol is added to the fermented medium and agitation and aeration continued at the same rate. The resulting broth is filtered and the cells reserved for further treatment, is extracted with three 15 liter portions of n-propyl acetate. The combined extracts are washed with one liter of 3% sodium bicarbonate and one liter of water and concentrated to dryness in vacuo (broth extract).

The broth extract containing the IS-hy-droxy derivative of the product of Example 1 is chromatographed on silica gel. The five 100 ml. fractions which were eluted with 2% methanol in chloroform were evaporated to dryness leaving as a residue a crude material containing the product. This material is dissolved in ethyl acetate and subjected to paper strip chromatography in the system benzene/formamide. The major component, with an Rf= 0.58 is eluted from the paper with methanol. The methanol solution is evaporated and the partially purified product which remains is partioned between water and chloroform. The chloroform phase which contains the product is separated and dried over sodium sulfate. The chloroform solution is filtered to remove the sodium sulfate and the filtrate containing the product evaporated to remove the chloroform and leave the partially purified product as a solid residue. This partially purified product is crystallized from ethyl acetate.

EXAMPLE 3 A solution of 400 mg. of the IS-hydroxy compound produced in Example 2 in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated in vacuo and the residual crystalline material is purified by crystallization to give the 3,2l-bis(2'-tetrahydropyranyl) ether of 3a,17a,2l-trihydroxypregnane-l1,15,20- trione.

EXAMPLE 4 n? mpg To a solution of 1.2 g. of the 3,2l-bis(2'-tetrahydropyranyl)ether produced in Example 3 in 75 cc. of alcohol is added 4 cc. of water and 1.0 cc. of concentrated EXAMPLE 5 OHzOH 50 of]: T 5113 1 10-- Fifty milligrams of 16 8-methyl-3ot,17ot,2l-trihydroxypregnane-l1,20-dione-21-acetate (Taub et al., J. Am. Chem. Soc., 82, 4012 (1960)) is dissolved in a mixture of 1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potassium hydroxide. The solution is allowed to stand for a period of about ten minutes at room temperature. It is then acidified with acetic acid. The benzene is evaporated in vacuo and the residual material is crystallized from ethyl acetate and ether to give 16,B-methyl-3a,17a, 21-trihydroxypregnane-1 1,20-dione.

Similarly, when the corresponding 16,8-ethyl, 16,8- propyl or 16fl-butyl-3ot,17u,2l-trihydroxypregnane-11,20- dione-21-acetate (prepared by the method of Taub et al. using diazoethane, diazopropane or diazobutane in place of diazomethane) is substituted for the 16fl-methyl compound in the above procedure, the corresponding 16-alky1 products are obtained.

EXAMPLE 6 To a stirred solution of 500 mg. of 16;3-methyl-3a,17a, 21-trihydroxypregnane-11,20-dione in 12.5 ml. of methanol and 3 ml. of dimethylformamide under nitrogen is added a slurry of 680 mg. of semicarbazide hydrochloride and 370 mg. of sodium bicarbonate in 1 ml. of water. The stirred mixture is refluxed three and one-half hours and maintained at 45 C. for 17 hours. It is then cooled to 20 C. and 50 ml. of 50% saturated aqueous sodium chloride is added and after two hours at 0 C. the precipitate of the ZO-semicarbazone of 16fi-methyl-3a,17a,21- trihydroxypregnane-l1,20-dione is filtered, washed with water until free of chloride ion and dried in air. The corresponding 16-higher alkyl compounds are obtained when the other products of Example 5 are substituted in the above procedure for the 16fl-methyl compound used above.

EXAMPLE 7 CHaOAc A solution of 500 mg. of the ZO-semicarbazone of 16 3- methyl 30,17o,21 trihydroxypregnane-l1,20-dione in 10 ml. of acetic acid and 0.5 ml. of acetic anhydride is heated at reflux in an atmosphere of nitrogen for one hour. The reaction mixture is cooled and 13 ml. of Water is added. The mixture is heated on a steam bath for 5 hours and the mixture is then concentrated nearly to dryness in vacuo. Water and chloroform are added. The mixture is thoroughly extracted with chloroform and the combined chloroform extracts are washed with excess saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is then removed by distillation in vacuo. The residue is chromatographed on neutral alumina from which the pertinent benzenechloroform eluates yield 16-methyl-3a,21-dihydroxy-16- pregnene-l1,20-diol-3,2l-diacetate.

The corresponding 16-ethyl, propyl and butyl compounds are obtained when the higher alkyl products of Example 6 are used as the starting material in the above procedure.

EXAMPLE 8 CI-IzOAc To a stirred solution of 500 mg. of 3oe,21-dihydroxy- 16-methyl-l6-pregnene-11,20-dione 3,21 diacetate in 15 ml. of methylene chloride at 0 C. are added 8 g. of disodium hydrogen phosphate and 2 ml. of 2 M peroxytrifluoracetic acid in methylene chloride. After minutes at 0 C. and 25 for one hour, water is added and the mixture thoroughly extracted with methylene chloride.

The latter extract is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent and crystallization of the residue from acetone-ether gives 3a,21-dihydroxy-16fi-methyl- 16a,17u-0xido-pregnane-11,20-dione-3,2l-diacetate.

The corresponding 16-ethyl, propyl and butyl compounds are obtained when the higher alkyl products of Example 7 are used in the above procedures as the starting material.

EAXAMPLE 9 OHzOAc :00 01 l- 5m AcO-- To a stirred solution of 800 mg. of 16-methyl-16a,17aoxide (product of Example 8) in 10 ml. of glacial acetic acid at 15 C. is added 10 ml. of 7% hydrogen chloride in acetic acid at 15 (Alternatively, similar results are obtained with 800 mg. of 16-methyl-16a,17a-oxide in 5 ml. of acetone and 1 ml. of concentrated hydrochloric acid cooled to 1015). In either case after 20 minutes at 10-15 water is added and the solid product is filtered, Washed with water and dried in air to give a mixture of the corresponding A -16-methy1 and 16-methylene steroids. This mixture is separated into its components by chromatography on Whatman #3 filter paper (40 mg. per 6" x 20" sheet) utilizing formamide as the stationary phase and chloroform benzene 1:9 as the mobile phase. The appropriate band as indicated by blue tetrazolium reagent is cut out, eluted with methanol, and the methanol concentrated to dryness in vacuum. Water is added to the residue, the solid filtered, washed with water and dried in air. Pure crystalline material is obtained in each case by crystallization from ethyl acetate-hexane or acetone-ether. The product obtained from 3a,21-dihydroxy- -methyl-16u,17a-oxidopregnane 11,20 dione-3,21- diacetate is a mixture of 3a,17a,2l-trihydroxy-16-methyl- IS-pregnene-l1,20-dione-3,2l-diacetate, and 3a,17oc,21 trihydroxy-l6-rnethylene-pregnane 11,20 dime-3,21- diacetate which is separated as described above. Similar- 1y, when the 16-ethy1, propyl or butyl compounds of Example 8 are used instead of the 16-methyl compounds in the above procedure, similar mixtures of compounds having the corresponding 16-higher alkyl group are obtained.

EXAMPLE 10 CHzOAc o 0 '-----0 o T'om l Br AeO-C To a stirred solution of 1.00 g. of 3a,21-diacetoxy-16- methyl-1S-pregnene-lh-ol-l1,20-dione in 50 ml. of t-butanol and 6 ml. of water is added 1.00 g. of N-brom-succinimide. After five hours at 25 aqueous sodium sulte is added until the solution is colorless. The t-butanol is removed in vacuo, water (50 ml.) is added and the crystalline reaction product, 3a,2l-diacetoxy-15/3-bromo-16a, 17a-oxido-16B-methyl-pregnane-11,20-dione is filtered, washed with water and dried in air. The corresponding 16-ethyl, propyl and butyl compounds are obtained by using the higher alkyl products of Example 9 in the above procedure instead of the methyl compound.

EXAMPLE 1 l omoAc (:10 o 'fiorn NW Br AcO C To a stirred solution of 5.05 g. of 3a,21-dihydroxy-16/3- methyl 16a,17a oxido pregnane 11,20 dione 3,21- diacetate in 75 ml. of acetic acid maintained at 1015 C., there is added 25 ml. of cold 15% hydrogen bromide in acetic acid. After 35 minutes, the mixture is concen- 27 trated to dryness in vacuo and the residue is chromatographed on 200 g. of neutral alumina. From the petroleum ether-benzene eluates, there is obtained 16- methyl 3a,21 -dihydroxy 16 pregnene 11,20 dione- 3,21-diacetate, crystallized from acetone-ether.

The corresponding 16-ethyl, propyl, or butyl compound is readily obtained by using the higher alkyl products of Example 8 in place of the methyl compound in the above procedure.

EXAMPLE 12 GHnOAc The procedure of Example 8 is followed using as the starting material the 15-bromo-16-methyl-31a,21-dihydroxy-16-pregnene-11,20-dione3,2l-diacetate produced in Example 11 to yield the same compound as was obtained in Example 10. The corresponding 16-higher alkyl compounds are similarly obtained by starting with the 16- higher alkyl products of Example 11.

EXAMPLE l3 CHzOAc A mixture of 1.00 g. of the 15-bromo product of Example 12, 1.5 g. of potassium acetate, 1 g. of potassium iodide and 20 ml. of acetone is refluxed and stirred for 16 hours. The mixture is cooled, the inorganic salts removed by filtration and Washed with acetone. The combined Washes and filtrate are concentrated to dryness under vacuum and water (30 ml.) added to the residue. The crystalline slurry of 3u,15,21-triacetate is cooled to 0 and filtered, washed with water and dried in air.

The corresponding 16-ethyl, propyl and butyl products are obtained by using in the above procedure the 16-higher alkyl products of Example 12 in place of the methyl compound.

EXAMPLE 14 CHzOAc O IS Jm i, t... AcO- i A solution of 1.00 g. of the triacetoxy oxido-pregnane product of Example 13 in 10 ml. of acetic acid containing hydrogen chloride is kept at 25 for two hours. The

28 solution is concentrated to dryness under vacuum to give a residue consisting primarily of 3a,15,21-triacetoxy-17ahydroxy-l6-methyl-15-pregnene-11,20-di0ne. The corresponding l6-ethyl, propyl and butyl compounds are similarly prepared from the higher alkyl derivatives.

EXAMPLE 15 (|)H20H t zmorr 30 00 To a solution of the product of Example 14 (800 mg.) in 200 ml. of methanol is added 500 mg. of sodium hydroxide in 10 ml. of water. After two hours at 25 the solution is neutralized with acetic acid, the methanol removed under vacuum and the mixture extracted with chloroform. The chloroform extract is Washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated to dryness under a vacuum. The residue which consists of a mixture of 16a and 16/3-methyl pregnanes is separated into its components by chromatography on Whatman #3 filter paper, utilizing formamide as the stationary and chloroform as the mobile phase. Similar mixtures of 16a and B-ethyl, propyl and butyl products are similarly prepared, using the proper 16-alkyl starting material in the above procedure.

EXAMPLE 16 Twenty-four grams of l6a-methyl-3,17a,21-trihydroxypregnane-l1,15,20-trione, 910 ml. of chloroform, 237 ml. of concentrated hydrochloric acid and 237 ml. of 37% formaldehyde are combined and stirred at room temperature for 70 hours. The chloroform layer is separated and the aqueous layer is extracted twice with 50 ml. of chloroform. The combined chloroform solutions are then washed twice successively with 200 ml. of Water, 200 ml. of saturated sodium bicarbonate solution and 200 ml. of water. The chloroform solution is dried over magnesium sulfate and concentrated in vacuo to give crystals. These are flushed with ml. of methanol to remove all the chloroform and then sufiicient methanol to dissolve the crystals is added. The methanol solution is concentrated in vacuo to a thick slurry and cooled to 0-5. The mixture is then filtered, and the precipitate is Washed twice With 15 ml. of cold methanol and dried in vacuo at 50. The product can be recrystallized from methanol. It is the 17,21-bismethylenedioxy derivative of 16a-methyl-3a-17oc,2l-trihydroxypregnane-l1,15,20-trione (Compound U).

The corresponding 16,8-methyl and 16a and [Si-ethyl, propyl and butyl compounds are similarly prepared by using the corresponding 16-substituted compounds from Example 15 in the above procedure.

EXAMPLE 17 Butyl lithium (10 m1. of a l N ether solution) is added to a stirred suspension of 3.6 g. of methyl triphenylphosphouium bromide [prepared from methyl bromide and triphenylphosphinesee G. Wittig and U. Schollkopf, Chem. Ber. 87, 1318 (1954)] in 50 ml. of ether under nitrogen. The mixture is stirred two hours, following which 1.00 g. of the bismethylenedioxy derivative of 3a,17ot,21-trihydroxy-16a-methylprcgnane 11,15,20 trione in 100 ml. of ether is added. The mixture is stirred 18 hours, water is added and then extracted with chloroform. The chloroform extract is washed with dilute hydrochloric acid, water and dried over magnesium sulfate. The solvent is removed under vacuum and the residue crystallized from acetone-ether.

The lfi-methyl-lS-methylene compound is obtained similarly, as are the 16st and fi-ethyl, propyl or butyl-lS- methylene compounds by using the proper 16-alkyl compound from Example 16 in the above procedure.

When ethyl, propyl or butyl triphenylphosphonium bromide is substituted for the methyl compound in the above procedure, using any of the l6-alky1 products of Example 16 or the 15-keto steroid of Example 4 as the starting material, the corresponding 15-alkylidenyl compound is produced.

A solution of 500 mg. of the 16a-methyl-15-methylene product of the previous example is hydrogenated over 100 mg. of 5% palladium on charcoal catalyst in 15 ml. of ethyl acetate. Following uptake of 1 equivalent of hydrogen the catalyst is filtered, washed with ethyl acetate and the filtrate and washings concentrated to dryness. The residue is a mixture of 15a,16a and 155,16a-dimethylpregnanes which is separated into its components by chromatography in Whatman #3 filter paper using formamide as the stationary and 1:1 benzene-cyclohexane as the mobile phase.

Similar reduction of the l6B-methyl-lS-methylenebismethylenedioxy prepared as described in Example 17, gives the corresponding l5a,l6B-dimethyl and l5,B,l6;8-dimethyl-bis-methylene dioxy derivatives. When the other 15-alkylidenyl-l6-alkyl steroids and l5-alkylidenyl steroids of Example 17 are similarly treated by the above procedure, the corresponding 15,16-dialkyl-bismethylenedioxy steroids are obtained.

EXAMPLE 19 A solution of 400 mg. of the 17,2l-bismethylenedi0xy derivative of 15a,16ot-dimethyl-3a,17u,21-trihydroxypregnane-lLZO-dione in 4 ml. of pyridine is added to the complex formed by the addition of 400 ml. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and allowed to stand at room temperature overnight. The reaction mixture is then poured into water and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The solvent layer is then dried and the solvents are removed by vacuum evaporation. The residual crystalline material is purified by crystallization from ethyl acetate-ether to give the 17,21-bisrnethylenedioxy derivative of 15a,16a-dimethyl-17a,2l-dihydroxypregnane- 3,11,20-dione.

When the other 15-alkyl and 15,16-dialkyl steroids of Example 18 are substituted for the 15u,16a-dimethyl steroid in the above procedure, the corresponding S-keto product is obtained.

EXAMPLE 20 CHzOAc A slurry of 970 mg. of the product of Example 19 in 97 ml. of 60% formic acid is six times purged with nitrogen and then heated on a steam cone for 15 minutes under nitrogen. After about five minutes, the compound is completely in solution. It is cooled in an ice bath and 100 ml. of water is added. There is then added gradually 20 g. of sodium carbonate over approximately 20 minutes. This results in a gummy precipitate which is extracted with chloroform. The chloroform solution is washed acid-free with saturated sodium bicarbonate and then with water. The chloroform is removed in vacuo and the residue is flushed with 20 ml. of methanol and then concentrated in vacuo to dryness.

The crude product is dissolved in 45 ml. of purified methanol and purged six times with nitrogen. After add ing 1.43 ml. of 0.21 M sodium methoxide in methanol, the solution is stirred for seven minutes at 2025 under nitrogen. It is then acidified with 3-4 drops of acetic acid, 5 ml. of water and 500 mg. of Darco 6-60 are added and the mixture is stirred at room temperature for 20 minutes. The charcoal is filtered and 40 ml. of water is added. The solution is concentrated in vacuo to essentially no methanol. The product, :,16ot-di1'I1GIhYl-l7a, 2l-dihydroxypregnane-3,11,20-trione, is filtered and dried. When the other 15-alkyl and 15,16-dialkyl steroids of Example 19 are used inthe above procedure in place of the 31 la,l6a-dimethyl compound, the corresponding 3-keto- 15-alkyl-l7a,2l-dihydroxy steroid is obtained.

To a solution of 100 mg. of this product in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is heated on a steam bath for 15 minutes. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted into ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is then dried with anhydrous sodium sulfate, following which the solvent is removed in vacuo, and the residue is chromatographed on alumina. The product is isolated by crystallization (acetone-ether) of the appropriate benzene eluates.

When the other 15-alkyl compounds described above are similarly treated, the corresponding 21-acetates are obtained. Similarly, when propionic anhydride is substituted for acetic anhydride, the corresponding 21-propionate is obtained.

EXAMPLE 21 onto. o0

-orr 07 Torr; 1 --CHa O To a stirred solution of 630 mg. of 17a,21-dihydroxy- 15 a,16a-dimethyl-3,1 1,20-pregnanetrione-2 l-acetate in ml. of acetic acid and 8 ml. of chloroform kept at -10 C. is added 240 mg. of bromine in 6 ml. of chloroform. After addition is complete, 12 g. of sodium acetate in 7 ml. of cold water is added. Additional water is added and the mixture is extracted with chloroform. The chloroform extract is washted with dilute potassium bicarbonate, water and dried over sodium sulfate. The residue is triturated with ether to give crystalline 4-bromo- 17a,21-dihydroxy-15a,16ot-dimethyl 3,11,20 pregnanctrione 2l-acetate.

When the other -alkyl and 15,16-dialkyl steroid 21- alkanoates of Example are used in the above procedure, the correspondingly substituted products are obtained.

EXAMPLE 22 ornoAc Example 21 are similarly used in the above procedure, the correspondingly substituted 3-semicarbazones are obtained.

EXAMPLE 23 0 1120 Ac ,5 0 O= \'j 'i... r ,1 to

Five hundred mg. of the semicarbazone of 17a,21-dihydroxy-15a,l6a-dimethyl-4-pregnene-3,11,20 trione 21- acetate is dissolved in 20 ml. of acetic acid, 1.5 ml. of pyruvic acid and 5 ml. of water. After 18 hours at 25 C., water is added and the mixture is extracted with chloroform. The chloroform extract is washed with aqueous potassium bicarbonate, water, and dried over sodium sulfate. Removal of the solvent gives crude 17u,21-dihydroxy 15a,16a-dimethyl-4-pregnene-3,l1,20-trione 2lacetate which is purified by crystallization from acetoneether.

When the other 15-alkyl and 15,16-dialkyl products of Example 22 are used in the above procedure, the correspondingly substituted compounds are obtained. Among the products so prepared are 17a,2l-dihydroxy- 15a,l6fi-dimethyl,l5/3,16a-dimethyl, 1519,1613 dimethyl, 15a-methyl, lid-methyl, ISm-ethyl, l5a,16B-diethyl, L- methyl-16fi-ethyl, l5,8,l6,8-diethyl, 155,16fi-dipropyl and 155,163 dibutyl-4-pregnene-3,11,20-trione-2l-acetates or propionates. 9

EXAMPLE 24 A solution of 500 mg. of 17u,21-dihydroxy-150,16otdimethy1-4-pregnene-3,11,20-trione 21-acetate in 15 ml. of methanol is treated with 500 mg. of potassium bicarbonate in 5 ml. of water under nitrogen at reflux for 10 minutes. The mixture is cooled, neutralized with 0.5 ml. of acetic acid in 5 ml. of water, the methanol removed in vacuo and the product extracted into ethyl acetate. Concentration of the ethyl acetate gives crystalline 17a, 21-dihydroxy 1506,1606 dimethyl-4-pregnene-3,11,20-trione.

When the other 15-alkyl and 15,16-dialkyl products of Example 23 are substituted in the above procedure for the 15a,l6a-dimethyl steroid, the corresponding steroids are obtained.

EXAMPLE 25 33 To a stirred solution of 500 mg. of 17a,21-di-hydroxy l5ot,16u-dimethyl-4-pregnene-3,l1,20-trione in 12.5 ml. of methanol and 3 ml. of dimethylformamide, kept under nitrogen, is added a slurry of 680 mg. of semicarbazide hydrochloride and 370 mg. of sodium bicarbonate in 1 ml. of water. The stirred mixture is refluxed 3 /2 hours and maintained at 45 C. for 17 hours. to 20 C. and 50 ml. of 50% saturated aqueous sodium chloride is added. After two hours at C. the precipitate of the 3,20-disemicarbazone of 17a,21-dihydroxy- 15a,l6a-dimethyl-4-pregnene 3,11,20 trione is filtered, washed with water until free of chloride ion and dried in am When the other IS-alkyl and 15,16-dialkyl steroids in Example 24 are substituted for the 15a,16a-dimethyl compound in the above procedure, the correspondingly substituted product is obtained.

EXAMPLE 26 Tie a stirred solution of 600 mg. of the 3,20-disemioarbazone of 17,21 dihydroxy 15 a,16a-dimethyl-4-pregnone-3,11,20-trione in 30 ml. of tetrahydrofuran and 11 ml. of water under nitrogen is added 200 mg. powdered sodium borohydride. The stirred suspension is refluxed 45 minutes and then cooled to 15 C. Aqueous acetic acid (3 ml. of 30%) is added cautiously and most of the tetrahydrofuran is removed in vacuum. Addition of 5 ml. of methanol and 5 of water induces the product to crystallize. FOllOWlIlg addition of ml. of a saturated sodium chloride solution and aging at 0 C. the product, 3,20-disemicarbazone of 11p,17a,21-trihydroxy- 15 a,l6wdimethyl-4pregnene-3,20-dione is filtered, washed with water and dried in air.

Similarly, the other 15-alkyl and 15,16-dialkyl steroids of Example 25, when used in the above procedure, give the corresponding 3,20-disemicarbazones.

EXAMPLE 27 CHzOH To a solution of 510 mg. of the 3,20-disemicarbazone of 11B,l7oz,2l trihydroxy-15a,16a-dimethyl-4-pregnene 3,20-dione in 5 ml. of acetic acid is added 1.20 ml. of Water and 0.50 ml. of pyruvic acid. The solution is kept at 25 C. for 18 hours. Water (20 ml.) is added, and the mixture is extracted thoroughly with chloroform. The chloroform extract is dried over magnesium sulfate and taken to dryness. The residue is crystallized from acetone-ether to give pure l1B,17a,21-trihydroxy15u,16adimethyl-4-pregnene-3,20-dione. The other 15-alkyl and 15,16-dialkyl steroids of Example 26, when :used in the above procedure, similarly yield the corresponding 1118- hydroxy compounds.

It is then cooled The procedure :of Example 16 is followed using the product of Example 26 as the starting material. There is thus obtained the 17,2.l-bismethylenedioxy of 1504,16u-dimethyl-11,8,17a,21-trihydroxy-4 pregnane 3,20 dione. The corresponding products are similarly prepared from the other 15-alkyl and 15,16-dialkyl products of Example 27.

EXAMPLE 29 /OCH2 H2C\ I o-o-o HO CH3 "CH3 CH3" To 8.0 g. of the product of Example 28 suspended in 100 ml. of t-butyl alcohol is added 3.2 g. of sodium methylate. To this mixture under nitrogen is added 5 ml. of diethyl oxalate and the mixture is stirred under nitrogen for six hours. The mixture is then cooled and ether is added. The product is filtered.

A mixture of the above product, 13 g. of anhydrous potassium carbonate, 300 ml. of acetone and 50 ml. of methyl iodide is refluxed 20 hours. The mixture is filtered hot and the filtrate concentrated to a small volume. A large amount of Water is then added to the concentrate and the mixture is extracted with ethyl acetate. The extract is Washed with satunated sodium chloride solution and dried. Activated charcoal is added and the mixture is filtered. Evaporation of the filtrate yields a. crude intermediate.

The crude intermediate thus prepared is dissolved in 250 ml. of absolute alcohol and 1.0 g. of sodium methylate is added. The mixture isallowed to stand at room temperature for four hours. i A few drops of acetic acid and 20 ml. of Water is added andthe methanol is removed under reduced pressure at a temperaturenot exceeding 35. The ethyl acetate extract of the mixture is washed to neutrality with a saline solution, dried and decolor-ized with activated carbon to give the crude .17- bismethylenedioxy) derivative of 2-a;l5u,l6oc-tnimethyl- 1 1 B, 17a,21atrihydroxy-4-pregnehe-3,20-dione:

When ethyl iodide, propyl bromide. or butyl bromide is substituted in the above procedure for methyl iodide, the corresponding 2-ethyl, propyl and butyl compounds starting material in the above procedure, the correspond ing 2a,15-dialkyl and 2a,15,16-trialkyl steroid is obtained.

EXAMPLE 30 (fI-IzOH o ---on no Ton. 0H; CH3" i A slurry of 970 mg. of the product of Example 29 in 97 m1. of 60% formic acid is purged six times with nitnogen and then heated on a steam cone for minutes under nitrogen. The reaction mixture is cooled in an ice bath and 100 ml. of water is added. There is then added g. of sodium carbonate (in approximately 20* minutes). A gummy precipitate appears which is extracted with chloroform. The chloroform solution is washed acid free with saturated sodium bicarbonate once and then washed with Water. The chloroform is removed in vacuo and the residue flushed with 20 ml. of methanol and then concentrated to dryness in vacuo. The crude product is then dissolved in 45 ml. of purified methanol and purged six times with nitrogen. There is then added 1.43 ml. of 0.21 M sodium methoxide solution in methanol. The solution is stirred for seven minutes at 2025 under nitrogen. It is then acidified with 3-4 drops of acetic acid. There is then added 5 ml. of water and 500 mg. of charcoal. The mixture is stirred at room temperature for 20 minutes. The charcoal is removed by filtration and the filtrate is diluted with 40 ml. of water. The solution is then concentrated in vacuo to essentially no When the other 2a,15-dialkyl and 2ot,15,16-trialkyl droxy-4-pregnene-3,20-dione.

When the other 2a,l5-dialkyl and 2a,15,16-tralkyl products of Example 29 are used in the above procedure, the correspondingly substituted compound is obtained.

EXAMPLE 31 To a solution of 100 mg. of the product of Example 30 in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture heated on a steam bath for 15 minutes. A mixture of ice and water is then added and the reaction mixture is allowed to stand for about 30 minutes. The product is washed with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is then dried with anhydrous sodium sulfate, following which the solvent is distilled at about 40 C. in vacuo. The product is then crystallized from acetonehexane. The product is 2a,15,16t-trimethyl-l 113,17a-trihydroxy-4-pregnene-3,20-dione 21-acetate. The corresponding 2a,l5-dialkyl and 2a,15,16-trialkyl steroids are obtained by the above procedure using the other products of Example 30.

EXAMPLE 32 CI'IO AC (:30

C H's-- I u 0 H3 The procedure of Example 19 is followed using the product of Example 31 as the starting material. There is thus obtained 2a,15cc,l6ot-trimethyl-l7tx,21-dihydroxy-4- pregnene-3,ll,20-trione 2l-acetate. The ZI-acetates of the other products of Example 31 are similarly prepared.

EXAMPLE 33 anion 00 --011 o= Torn. on, CH3" The procedure of Example 24 is followed using the There L- (I312: .Qj

The procedure of Example 19 is followed using the product of Example 28, the 17,21-bismethylenedioxy derivative of 15 a,16a-dimethyl-1 1fl,17a,21-trihydroxy-4- pregnene-3,20-dione as the starting material. There is thus obtained the corresponding ll-keto compound of the above structure. Similarly, when the 17-bismethylenedioxy derivative of 2a,15a,-16a-trirnethyl-11,17a,21-trihydroxy-4-pregnene-3,20-dione (the product of Example 29) is used in the procedure of Example 19, the corresponding 3,11,20-trione is obtained. When the other 15- alkyl, 2,15 and 15,16-dialkyl and 2a,l5,l6-trialkyl compounds prepared in Examples 28 and 29 are used, the correspondingly substituted products are prepared.

Seventeen and one-half grams of the product of Example 34 is dissolved in 890 ml. of benzene and then 45 ml. of ethylene glycol and 1.87 g. of p-toluenesulfonic acid monohydrate added. The mixture is heated at reflux with stirring for 17.5 hours. The water being formed is continuously collected and removed. The solution is cooled to 20 and washed twice with 200 ml. of water followed by 200 ml. of saturated sodium bicarbonate solution and 200 ml. of water. Each wash is back extracted with benzene and the benzene is added to the batch. The dried benzene solution is then concentrated to dryness in vacuo. The residual product is refluxed with 100 ml. of ether for /2 hour and the mixture cooled. The product, the 3-dioxolane of the above structure, is isolated by filtration and washed with cold ether.

When the other -alky1, :,15 and 15,16-dialkyl and 2a,15,16-triall yl compounds prepared in Example 34 are used in the above procedure, the correspondingly substituted products are obtained.

EXAMPLE 36 A solution of 22.9 g. of the product of Example 35 in 200 m1. of benzene is added to 460 ml. of perbenzoic acid solution over approximately minutes while keeping the temperature at 2025. The mixture is allowed to stand about 48 hours at room temperature until over 100% of theory of the perbenzoic acid has been used. The solution is cooled to 10 and a 15% solution of sodium bisulfite is added with good agitation at less than 20 until a negative KI test is obtained. The aqueous phase is removed and the benzene washed acid-free with 5% sodium bicarbonate and then with water. The benzene solution is dried and concentrated in vacuo. The product (a mixture of oz and 13 isomers) is separated by chromatography on florosil. One gram of the mixture oxides is chromatographed on 1 00 g. of fiorosil. Elution with 5% acetone in hexane gives the 18 isomer. The a isomer is eluted with 10% acetone in hexane and recrystallized from a benzenehexane mixture.

When the other 15-alkyl, 2a,15 and 15,16-dialkyl and 2a,15,16-trialkyl compounds prepared in Example are used in the above procedure, the correspondingly substituted products are obtained.

EXAMPLE 37 One gram of the a-oxide produced in Example 36 is dissolved in 50 cc. of dry benzene and 50 cc. of dry ether. Freshly distilled boron trifluoride is added (0.83 cc.) and the clear solution is allowed to stand overnight at room temperature. The resulting yellow solution is added dropwise to cc. of saturated aqueous sodium bicarbonate with good stirring. The layers are separated and the organic layer is washed with saturated aqueous sodium bicarbonate and then with water and dried. The solution is evaporated to dryness in vacuo leaving a yellow oil which is purified by chromatography in 100 g. of florosil. The product is eluted with 3% acetone and hexane.

To a stirred solution of 600 mg. of the product obtained in 30 ml. of tetrahydrofuran and 11 ml. of water under nitrogen is added 200 mg. of powdered sodium borohydride. The stirred suspension is refluxed 45 minutes and then cooled. Aqueous acetic acid (3 ml. of 30%) is added cautiously and most of the tetrahydrofuran is removed in vacuo. Addition of 5 ml. of methanol and 5 ml. of water induces the product to crystallize. There is then added 10 ml. of saturated sodium chloride solution at 0 C. The intermediate product is then filtered, washed with water and dried in air.

Two hundred mg. of the product thus obtained is dissolved in 10 cc. of acetone and 10 mg. of p-toluene sulfonic acid monohydrate in 1 cc. of acetone is added. The solution is allowed to stand overnight at room temperature. It is then diluted with water and extracted with ether. The combined ether extracts are washed with water, dried and the solvent removed in vacuo. The residue is passed over 4 g. of acid washed alumina. The 17,21-bismethylenedioxy derivative of 6ocflll01'0150t,l6ocdimethyl 11fi,17oc,21 trihydroxy 4 pregnene 3,20- dione is removed in an 8:2 ether-chloroform solution. It can be recrystallized from methylene dichloride and ether.

When the other 15-alkyl, 211,15 and 15,16-dialkyl and 2a,15,16-trialkyl compounds prepared in Example 36 are used in the above procedure, the correspondingly substituted 6u-fluoro compounds are prepared.

EXAMPLE 38 The procedure of Example 30 is followed using as a starting material the product of Example 37. The product thus obtained is 6ot-fluoro,15a,16u-dimethy1- 39 11 3,17a,2l-trihydroxy-4-pregnene-3,20-dione. When the other compounds prepared in Example 37 are used in the procedure of Example 30, there are obtained 60:- fluoro 150a methyLISp methyl,2a,15a dimethyLZa, 15 8 dimethyl, 20:,1506160: trimethyl, 2a,15fi,16,8 trimethyl, 1506,16B dimethyl, 153,160: dimethyl, 156,161?- dimethyl, 15a,16a dimethyl, 20c ethyl 15a methyl, and 2a,15a diethyl 11B,l7ot,21 trihydroxy 4 pregnene-3,20-dione.

EXAMPLE 39 onion ---ort 0 'i T011. 1 "CH;

The procedure of Example 31 is followed using the product of Example 38 as the starting material. The

21-acetate thus formed is then oxidized by the procedure of Example 19 to form the ll-keto compound and this in turn is saponified by the procedure of Example 24 to yield 9a-fluoro-15a,16a-dimethyl-17a,2l-dihydroxy-4- 'pregnene-3,11,20-trione.

When the other products of Example 38 are used instead, the correspondingly substituted products are obtained.

Alternatively, the procedure of Example 37 with omission of the sodium borohydride reduction step, followed by removal of the 17,211-bismethylenedioxy grouping by the procedure of Example 30, may be used.

EXAMPLE 4O /OOH2 in 35 ml. of tetrahydrofuran and a solution of 750 mg.

of sodium borohydride in 20 ml. of water are each purged six times with nitrogen and then combined. The solution is then stirred at room temperature under nitrogen for 18 hours after which it is cooled to 0-5 A saturated solution of 4.7 g. of monobasic sodium phosphate is added over approximately 15 minutes. The slurry is then concentrated in vacuo to essentially no tetrahydrofuran while keeping the temperature below 45. The slurry is washed with water until neutral.

To a solution of 250 mg. of the product thus produced in 60 ml. of dry benzene under nitrogen is added 2.33 ml. of 3 M methylma-gnesium bromide in ether. The mixture is heated at 70 under nitrogen for hours and then cooled to 0-5". Ammonium chloride (5.6 g.) in 56 ml. of Water is added over approximately 20 minutes. The benzene is separated and the aqueous layer is extracted with two 20 ml. portions of benzene. The combined benzene solutions are washed neutral with water, dried with magnesium sulfate and concentrated to 4t) dryness. The crude product may be used in the next reaction, but, if desired, can be crystallized from ether, benzene or methanol.

A solution of 2 g. of the product thus formed in ml. of methanol is purged four times with nitrogen. 10.9 ml. of 8% sulfuric acid is added. The mixture is purged four times with nitrogen and then heated under nitrogen at reflux. The mixture is cooled to 05. A solution of 10.9 g. of sodium carbonate in 300 ml. of Water is added with cooling and good agitation. The gummy precipitate is extracted with chloroform and the extract is washed with water, dried and concentrated in vacuo. This crude product is used as is for the next reaction but can be recrystallized from methanol or ethanol.

A solution of 2 g. of the product thus obtained in 100 ml. of methanol is purged four times with nitrogen and then 4.2 ml. of 5% potassium hydroxide in methanol is added. The mixture is again purged four times with nitrogen. The solution is then cooled to 20 and acidified With a few drops of glacial acetic acid. Twenty-five ml. of water is added and the solution is concentrated in vacuo to essentially no methanol. The crystallized product is isolated by filtration, washed with Water and dried. It is the 17-bis-methylenedioxy derivative of 60:,15a,16oc-t1i methyl-1 lfl,l704,21-tril1ydroxy-4-pregnene-3 ,20-dione.

When the other l5-alkyl, 204,15- and 15,16-dialkyl and 2a,l5,l6-trialkyl products of Example 36 are used in the above procedure, the correspondingly substituted 6a-methyl compounds are obtained.

When the methylmagnesium bromide in the second paragraph of the above procedure is replaced by an equivalent amount of ethyl, propyl, or butyl magnesium bromide in any of the above procedures, the correspondingly substituted 6a-ethyl, propyl, and butyl compounds are obtained.

EXAMPLE 41 (IJH2OH (I30 i C Ha The procedure of Example 30 is followed using the product of Example 40 as the starting material to yield 6a,15a,l6a-trimethyl-11fl,17u,21-trihydroxy-4 pregnene- 3,20-dione. When the other compounds prepared in Example 40 are used instead, the correspondingly substituted product is obtained.

EXAMPLE 42 

1. COMPOUND OF THE FORMULA-- 